Two-way pump selectable valve and bypass waste channel

ABSTRACT

A delivery system for a sensor chip includes a plurality of selectable ports and a two-way pump port selectively connectable to each of the selectable ports. The two-way pump port is configured to allow material to be drawn or delivered from or to the two-way pump port. The delivery system also includes a chamber and a bypass waste channel that is selectively connectable to the two-way pump port. The plurality of selectable ports includes a selectable chamber port connected to the chamber and the chamber has a chamber waste exit. Material may selectively flow through the chamber to a waste collection via the chamber waste exit or flow to the waste collection via the bypass waste channel that bypasses the chamber waste exit.

CROSS REFERENCE TO OTHER APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/955,552, entitled TWO-WAY PUMP SELECTABLE VALVE AND BYPASS WASTECHANNEL, filed Apr. 17, 2018, now U.S. Pat. No. 10,837,440, which is adivisional of U.S. patent application Ser. No. 14/867,922, entitledTWO-WAY PUMP SELECTABLE VALVE AND BYPASS WASTE CHANNEL, filed Sep. 28,2015, now U.S. Pat. No. 9,970,437, which claims priority to U.S.Provisional Patent Application No. 62/084,379, entitled RADIAL VALVE,filed Nov. 25, 2014, all of which are incorporated herein by referencefor all purposes.

BACKGROUND OF THE INVENTION

Advances in micro-miniaturization within the semiconductor industry inrecent years have enabled biotechnologists to begin packingtraditionally bulky sensing tools into smaller and smaller form factors,onto so-called biochips. Often utilizing a biochip requires liquid, gas,or other substances to be deposited and removed in a controlled sequenceon or near the biochip. For example, various reagents and biologicalsamples are flowed over the biochip in a controlled sequence to preparethe biochip, perform a measurement using the biochip, and clean thebiochip for a next measurement. Manually performing this sequence isslow, error prone, and cost ineffective. Additionally, the transitioningfrom one measurement sample to a next measurement sample has beentypically inefficient due to the steps involved in cleaning, resetting,refilling, and replacing various components. It would be desirable todevelop items and techniques that are more efficient, robust, andcost-effective.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the invention are disclosed in the followingdetailed description and the accompanying drawings.

FIG. 1 illustrates an embodiment of a cell 100 in a nanopore-basedsequencing chip.

FIG. 2 illustrates an embodiment of a cell 200 performing nucleotidesequencing with the Nano-SBS technique.

FIG. 3 illustrates an embodiment of a cell about to perform nucleotidesequencing with pre-loaded tags.

FIG. 4 illustrates an embodiment of a process 400 for nucleic acidsequencing with pre-loaded tags.

FIG. 5 is a schematic diagram illustrating an embodiment of at least aportion of a biological sensor system.

FIG. 6 is a schematic diagram illustrating another embodiment of atleast a portion of a biological sensor cartridge system.

FIGS. 7A-7C are schematic diagrams illustrating another embodiment of atleast a portion of a biological sensor cartridge system.

FIG. 8A is a diagram illustrating an embodiment of a cartridge.

FIG. 8B is a diagram illustrating an embodiment of at least a portion ofinternal components of a cartridge.

FIG. 8C is a diagram illustrating an embodiment of a cartridge and aninstrument system that engages the cartridge.

FIG. 9 is a diagram illustrating another embodiment of at least aportion of internal components of a cartridge.

FIG. 10 is a schematic diagram illustrating an embodiment of a linearvalve.

FIG. 11 is a flowchart illustrating an embodiment of a process forflowing different types of materials (e.g., liquids or gases) throughthe cells of a nanopore-based sequencing biochip during different phasesof the biochip operation.

DETAILED DESCRIPTION

The invention can be implemented in numerous ways, including as aprocess; an apparatus; a system; a composition of matter; a computerprogram product embodied on a computer readable storage medium; and/or aprocessor, such as a processor configured to execute instructions storedon and/or provided by a memory coupled to the processor. In thisspecification, these implementations, or any other form that theinvention may take, may be referred to as techniques. In general, theorder of the steps of disclosed processes may be altered within thescope of the invention. Unless stated otherwise, a component such as aprocessor or a memory described as being configured to perform a taskmay be implemented as a general component that is temporarily configuredto perform the task at a given time or a specific component that ismanufactured to perform the task. As used herein, the term ‘processor’refers to one or more devices, circuits, and/or processing coresconfigured to process data, such as computer program instructions.

A detailed description of one or more embodiments of the invention isprovided below along with accompanying figures that illustrate theprinciples of the invention. The invention is described in connectionwith such embodiments, but the invention is not limited to anyembodiment. The scope of the invention is limited only by the claims andthe invention encompasses numerous alternatives, modifications andequivalents. Numerous specific details are set forth in the followingdescription in order to provide a thorough understanding of theinvention. These details are provided for the purpose of example and theinvention may be practiced according to the claims without some or allof these specific details. For the purpose of clarity, technicalmaterial that is known in the technical fields related to the inventionhas not been described in detail so that the invention is notunnecessarily obscured.

Nanopore membrane devices having pore sizes on the order of onenanometer in internal diameter have shown promise in rapid nucleotidesequencing. When a voltage potential is applied across a nanoporeimmersed in a conducting fluid, a small ion current attributed to theconduction of ions across the nanopore can be observed. The size of thecurrent is sensitive to the pore size.

A nanopore-based sequencing chip may be used for DNA sequencing. Ananopore-based sequencing chip incorporates a large number of sensorcells configured as an array. For example, an array of one million cellsmay include 1000 rows by 1000 columns of cells.

FIG. 1 illustrates an embodiment of a cell 100 in a nanopore-basedsequencing chip. A membrane 102 is formed over the surface of the cell.In some embodiments, membrane 102 is a lipid bilayer. The bulkelectrolyte 114 containing protein nanopore transmembrane molecularcomplexes (PNTMC) and the analyte of interest is placed directly ontothe surface of the cell. A single PNTMC 104 is inserted into membrane102 by electroporation. The individual membranes in the array areneither chemically nor electrically connected to each other. Thus, eachcell in the array is an independent sequencing machine, producing dataunique to the single polymer molecule associated with the PNTMC. PNTMC104 operates on the analytes and modulates the ionic current through theotherwise impermeable bilayer.

With continued reference to FIG. 1, analog measurement circuitry 112 isconnected to a metal electrode 110 covered by a thin film of electrolyte108. The thin film of electrolyte 108 is isolated from the bulkelectrolyte 114 by the ion-impermeable membrane 102. PNTMC 104 crossesmembrane 102 and provides the only path for ionic current to flow fromthe bulk liquid to working electrode 110. The cell also includes acounter electrode (CE) 116, which is an electrochemical potentialsensor. The cell also includes a reference electrode 117.

In some embodiments, a nanopore array enables parallel sequencing usingthe single molecule nanopore-based sequencing by synthesis (Nano-SBS)technique. FIG. 2 illustrates an embodiment of a cell 200 performingnucleotide sequencing with the Nano-SBS technique. In the Nano-SBStechnique, a template 202 to be sequenced and a primer are introduced tocell 200. To this template-primer complex, four differently taggednucleotides 208 are added to the bulk aqueous phase. As the correctlytagged nucleotide is complexed with the polymerase 204, the tail of thetag is positioned in the barrel of nanopore 206. The tag held in thebarrel of nanopore 206 generates a unique ionic blockade signal 210,thereby electronically identifying the added base due to the tags'distinct chemical structures.

FIG. 3 illustrates an embodiment of a cell about to perform nucleotidesequencing with pre-loaded tags. A nanopore 301 is formed in a membrane302. An enzyme 303 (e.g., a polymerase, such as a DNA polymerase) isassociated with the nanopore. In some cases, polymerase 303 iscovalently attached to nanopore 301. Polymerase 303 is associated with anucleic acid molecule 304 to be sequenced. In some embodiments, thenucleic acid molecule 304 is circular. In some cases, nucleic acidmolecule 304 is linear. In some embodiments, a nucleic acid primer 305is hybridized to a portion of nucleic acid molecule 304. Polymerase 303catalyzes the incorporation of nucleotides 306 onto primer 305 usingsingle stranded nucleic acid molecule 304 as a template. Nucleotides 306comprise tag species (“tags”) 307.

FIG. 4 illustrates an embodiment of a process 400 for nucleic acidsequencing with pre-loaded tags. At stage A, a tagged nucleotide (one offour different types: A, T, G, or C) is not associated with thepolymerase. At stage B, a tagged nucleotide is associated with thepolymerase. At stage C, the polymerase is in close proximity to thenanopore. The tag is pulled into the nanopore by an electrical fieldgenerated by a voltage applied across the membrane and/or the nanopore.

Some of the associated tagged nucleotides are not base paired with thenucleic acid molecule. These non-paired nucleotides typically arerejected by the polymerase within a time scale that is shorter than thetime scale for which correctly paired nucleotides remain associated withthe polymerase. Since the non-paired nucleotides are only transientlyassociated with the polymerase, process 400 as shown in FIG. 4 typicallydoes not proceed beyond stage B.

Before the polymerase is docked to the nanopore, the conductance of thenanopore is −300 pico Siemens (300 pS). At stage C, the conductance ofthe nanopore is about 60 pS, 80 pS, 100 pS, or 120 pS corresponding toone of the four types of tagged nucleotides. The polymerase undergoes anisomerization and a transphosphorylation reaction to incorporate thenucleotide into the growing nucleic acid molecule and release the tagmolecule. In particular, as the tag is held in the nanopore, a uniqueconductance signal (e.g., see signal 210 in FIG. 2) is generated due tothe tag's distinct chemical structure, thereby identifying the addedbase electronically. Repeating the cycle (i.e., stage A through E orstage A through F) allows for the sequencing of the nucleic acidmolecule. At stage D, the released tag passes through the nanopore.

In some cases, tagged nucleotides that are not incorporated into thegrowing nucleic acid molecule will also pass through the nanopore, asseen in stage F of FIG. 4. The unincorporated nucleotide can be detectedby the nanopore in some instances, but the method provides a means fordistinguishing between an incorporated nucleotide and an unincorporatednucleotide based at least in part on the time for which the nucleotideis detected in the nanopore. Tags bound to unincorporated nucleotidespass through the nanopore quickly and are detected for a short period oftime (e.g., less than 10 ms), while tags bound to incorporatednucleotides are loaded into the nanopore and detected for a long periodof time (e.g., at least 10 ms).

A fluid/gas delivery system for a sensor chip is disclosed. For example,a biological assay (e.g., nucleotide/nucleic acid sequencing) chiprequires fluids and/or gases to be provided on the sensor chip, and adelivery system provides at least a portion of the materials required toperform the assay. In some embodiments, a plurality of selectable portsare arranged on a first assembly. Each selectable port is incommunication with a separate channel. For example, each of the separatechannels are connected to a different reagent, liquid, gas, wastecontainer, etc. where material could be delivered/pushed ordrawn/pulled. One of the separate channels may be connected to a biochipand material could be delivered/pushed or drawn/pulled to/from thebiochip using this separate channel. A second assembly is movable inrelation to the first assembly and the second assembly has a channelthat is mechanically connectable to different ones of the plurality ofports on the first assembly by motion of the second assembly relative tothe first assembly. A mechanical interface is configured to engage anactuator so that relative motion of the first assembly and the secondassembly is affected by the actuator. For example, the second assemblyincludes a selection port that can be moved by an actuator/motor to beconnected to any one of the plurality of selectable ports that arearranged on the first assembly. In this example, the selection port maybe connected to only one port of the plurality of selectable ports ofthe first assembly at one time and the other selectable ports of thefirst assembly that are not connected to the selection port are sealedclosed (e.g., sealed by the second assembly). In some embodiments, theselection port of the second assembly is connected to a pump and achamber/channel that are utilized to deliver/push and/or draw/pullmaterials to/from the selected port of the plurality of selectable portsof the first assembly.

In some embodiments, any of the plurality of selectable ports can beselected to be connected to a two-way pump port. For example, a pump isconfigured to either draw or deliver fluid/gas from/to the two-way pumpport. A chamber is connected to a first chamber port that is included inthe plurality of selectable ports. For example, the first chamber portcan be selected to connect to the two-way pump port. The chamber is alsoconnected to a second chamber port. For example, the chamber includes abiochip and the first chamber port at least allows a reagent to enterthe chamber and the second chamber port at least allows the reagent toexit the chamber after passing through the biochip in the chamber. Awaste port is included in the plurality of ports. For example, aselection may be made to flow material to be discarded either throughthe second chamber port or to the waste port without passing through thesecond chamber port. For example, by having a two-way pump and aselectable waste port that allows waste to bypass the chamber, materialsthat ideally should not flow entirely through the chamber/biochip in anassay process may be discarded via the selectable waste port rather thana chamber port.

FIG. 5 is a schematic diagram illustrating an embodiment of at least aportion of a biological sensor system. For example, the biologicalsensor system is a nanopore-based nucleotide sequencing system.

The sensor system includes cartridge 502. Cartridge 502 engages with aninstrument system, interfaces with the instrument system, and functionstogether with the instrument system to perform a biological assay (e.g.,nanopore-based nucleotide sequencing). In FIG. 5, one or more of thecomponents shown to be not included in cartridge 502 may be included onthe instrument system. Cartridge 502 is removable from the instrumentsystem and another cartridge may be engaged with the instrument system.By utilizing a removable cartridge, the components of the cartridge maybe replaced quickly and easily on the instrument system without the needto clean and reuse the components of the cartridge. For example, thecartridge may be replaced for each different biological sample to beassayed by the instrument system.

Cartridge 502 includes biochip 504, radial valve 506, container 508,container 510 and container 512. Each of containers 508, 510 and 512 mayhold a liquid, a reagent, a gas, a solid (e.g., suspended in liquid) andany other substance to be utilized in performing a biologicalmeasurement. For example, container 508 holds a lipid and decane mix,container 510 holds a sample and pore/polymerase mix, and container 512holds a StartMix. Container 510 and container 512 are sensitive totemperature changes and thermal block 514 is thermally coupled tocontainers 510 and 512. For example, thermal block 514 provides thermalcooling to contents of container 510 and container 512. In someembodiments, thermal block 514 provides thermal heating and/or coolingto raise, lower, and/or maintain a temperature of contents of container510 and container 512. In the example shown, thermal block 514 is not apart of cartridge 502 and is a part of the instrument system. Biochip504 may be the nanopore-based sequencing chip described elsewhere in thespecification. Biochip 504 is electrically connected/interfaced with theinstrument system and electrical measurement data is read from biochip504 and exported out of the biochip 504 to the instrument system forstorage/analysis. For example, cartridge 502 includes a circuit boardthat provides electrical contact interfaces between biochip 504 and theinstrument system. Biochip 504 is thermally coupled to the instrumentsystem via a thermoelectric cooler (TEC)/heat sink assembly 516. TheTEC/Heat sink assembly 516 allows the temperature of the biochip 504 tobe controlled. For example the biochip and its fluid contents can beheld at a constant temperature (e.g., warm or cold) and/or exposed tovarying temperatures in a controlled manner (e.g., thermal cycling).

Radial valve 506 mechanically engages actuator/motor 518 of theinstrument system. Actuator/motor 518 is separate from cartridge 502.Motor 518 actuates a movable assembly of radial valve 506 to select adesired port of radial valve 506. For example, motor 518 engages amovable assembly of radial valve 506 directly or indirectly via one ormore gears, worm screws, or friction engagements (e.g., friction wheel).

Radial valve 506 includes central port 520 and selectable ports 521-526that are arranged coaxially in a rotary configuration. Radial valve 506may be rotated via actuator/motor 518 to select one of selectable ports521-526 as the active/open port. The other not selected ports ofselectable ports 521-526 may or may not be automatically sealed/closedwhen the selected port is selected. Materials may be passed betweencentral port 520 and the selected port. For example, a fluid/gas passagechannel is created between central port 520 and the selected port.Central port 520 is connected to interface 528 via a channel (e.g.,tube). Interface port 528 is an interface of cartridge 502 wherematerials may enter/exit cartridge 502. Examples of interfaces of thecartridge include a needle septum, a flap valve or a ball displacementvalve. Central port 520 is connected to pump 530 via interface 528. Pump530 includes a syringe pump that may draw or push content into or out ofpump chamber 532. Pump 530 includes a secondary radial value 534. Insome embodiments, chamber 532 is a fluidic channel such as tubing. Pump530 is a two-way pump that can deliver/push and draw/pull materials into/out of pump chamber 532.

Radial valve 534 may be configured to connect pump chamber 532 to any ofselectable ports A-F as shown in FIG. 5. Radial valve 534 may be rotatedvia an actuator/motor to select one of selectable ports A-F as theselected active/open port. The other not selected ports of selectableports A-F are automatically sealed/closed when the selected port isselected. Liquid/gas may be passed between pump chamber 532 and theselected port of valve 534. Port A is connected to a salt buffersolution. Port B is connected to a surfactant solution. Port C isconnected to ethanol. Port D is connected to central port 520 viainterface 528. For example, when port D is selected on radial valve 534,pump 530 is able to deliver/push any material in pump chamber 532 to aselected port of radial valve 506 and pump 530 is able to pull anymaterial from the selected port of radial valve 506 into chamber 532.Port E is connected to a waste container where content in chamber 532can be discarded. Port F is connected to an air vent. For example,ambient air can be drawn into chamber 532 when port F is selected onradial valve 534. In an alternative embodiment, rather than utilizingtwo radial valves, a single radial valve on cartridge 502 is utilized.For example, valve 506 may include additional ports for additionalreagents and central port 520 is connected to pump chamber 532 withoutanother intervening radial valve.

In some embodiments, by delivering/pushing and drawing/pulling variousmaterials to/from the ports of radial valve 534 and/or radial valve 506using pump 530 in a configured sequence, a biological assay is performedusing biochip 504. For example, a reagent to be pushed into chip 504 maybe placed in chamber 532 by selecting one of selectable ports A-C onvalve 534 connected to a desired reagent, pumping content of theselected port into chamber 532, then selecting port D on valve 534 andselecting port 521 on valve 506, and pushing the content of chamber 532to chip 504. In another example, a reagent to be pushed into chip 504may be placed in chamber 532 by selecting port D on valve 534 andselecting one of selectable ports 522-524 on valve 506 connected to thedesired reagent, pumping content of the selected port into pump chamber532, then selecting port 521 on valve 506 and pushing the content ofchamber 532 to chip 504. In another example, a reagent to be pushed intochip 504 may be drawn out of chambers 508, 510 or 512 by selecting thecorresponding port 524, 523 or 522, and selecting port D on valve 534.In this example, a reagent is drawn into fluid channel 527, but not pastfluid interface 528 which keeps the reagent within the cartridge anddoes not contaminate surfaces outside of the cartridge (e.g. pumpchamber 532). Port 521 can then be selected on valve 506, and thereagent can be pushed into the chip 504. Often in the sequence, amaterial flowed on chip 504 needs to be discarded as a next material isflowed on chip 504. Interface 536 is an interface of cartridge 502 wherewaste materials to be discarded may exit cartridge 502. Material in thechamber of chip 504 may be pushed out of the chamber and into wastecontainer 538 via chamber exit port 535 and interface 536. However insome cases, it may be desirable to be able to discard material withoutflowing the material to be discarded completely across chip 504 and outchamber port 535. In some embodiments, port 521 is selected on valve 506and pump 530 pulls material out of the chamber of chip 504. Then port526 is selected and the material to be discarded in pump chamber 532 ispushed out into waste container 538 via an alternative channel path thatdoes not enter the chamber of chip 504 and does not include chamber port535 yet still exits via interface port 536. Other materials pumped fromother sources by pump 530 to be discarded may also be pushed into wastecontainer 538 bypassing chip 504 via the alternative channel path.Examples of waste container 538 include a vented container, anexpandable container, a one-way valve container, and an absorbentmaterial filled container (e.g., to prevent flow back onto chip 504). Inan alternative embodiment, waste container 538 is included in cartridge502.

The embodiment shown in FIG. 5 is merely an example and has beensimplified to illustrate the embodiment clearly. For example, the radialvalves shown in FIG. 5 may include any number of selectable ports.Additional components not shown in FIG. 5 may also exist.

FIG. 6 is a schematic diagram illustrating another embodiment of atleast a portion of a biological sensor cartridge system. For example,the biological sensor cartridge system is a nanopore-based nucleotidesequencing system.

The sensor system includes cartridge 602. Cartridge 602 engages with aninstrument system, interfaces with the instrument system, and functionstogether with the instrument system to perform a biological assay (e.g.,nanopore-based nucleotide sequencing). In FIG. 6, one or more of thecomponents shown to be not included in cartridge 602 may be included onthe instrument system. Cartridge 602 is removable from the instrumentsystem and another cartridge may be engaged with the instrument system.By utilizing a removable cartridge, the components of the cartridge maybe replaced quickly and easily on the instrument system without the needto clean and reuse the components of the cartridge. For example, thecartridge may be replaced for each different biological sample to beassayed by the instrument system.

Cartridge 602 includes biochip 604 in a chamber, radial valve 606, andcontainers 608, 610, 612, 640, 642, and 644. Each of containers 608,610, 612, 640, 642 and 644 may hold a liquid, a reagent, a gas, a solid(e.g., suspended in liquid), and any other substance to be utilized inperforming a biological measurement. For example, container 608 holds alipid and decane mix, container 610 holds a sample and pore/polymerasemix, container 612 holds a StartMix, container 640 holds ethanol,container 642 holds a surfactant solution, and container 644 holds asalt buffer solution. In some embodiments, container 610 and container612 are sensitive to temperature changes and a thermal block providesthermal heating and/or cooling to raise, lower, and/or maintain atemperature of contents of container 610 and container 612. Biochip 604may be the nanopore-based sequencing chip described elsewhere in thespecification. Biochip 604 is electrically connected/interfaced with theinstrument system and electrical measurement data is read from biochip604 and exported out of the biochip 604 to the instrument system forstorage/analysis. For example, cartridge 602 includes a circuit boardthat provides an electrical contact interface between biochip 604 andthe instrument system. Biochip 604 is thermally coupled to theinstrument system via TEC/heat sink assembly 616. TEC/heat sink assembly616 allows thermal energy of biochip 604 to be dissipated via assembly616.

Radial valve 606 mechanically engages actuator/motor 618 of theinstrument system. Actuator/motor 618 is separate from cartridge 602.Motor 618 actuates a movable assembly of radial valve 606 to select adesired port of radial valve 606. For example, motor 618 engages amovable assembly of radial valve 606 directly or indirectly via one ormore gears, worm screws, or friction engagements (e.g., friction wheel).

Radial valve 606 includes central port 620 and selectable ports 621-628that are arranged coaxially in a rotary configuration. Radial valve 606may be rotated via actuator/motor 618 to select one of selectable ports621-628 as the active/open port. The other not selected ports ofselectable ports 621-628 are automatically sealed/closed when theselected port is selected. Selectable port 628 is connected to an airvent. For example, ambient air can be drawn into chamber 632 when port628 is selected on radial valve 606. Materials may be passed betweencentral port 620 and the selected port. For example, a fluid/gas passagechannel is created between central port 620 and the selected port.Central port 620 is connected to pump chamber 632. In some embodiments,the pump chamber is located external to cartridge 602 and central port620 is connected to the external pump chamber via an interface port ofcartridge 602 connected to central port 620 via a channel (e.g., tube).Pump chamber 632 is a part of a two-way syringe pump that may draw orpush content into or out of pump chamber 632. In some embodiments, pumpchamber 632 is a fluidic channel such as tubing.

A piston of pump chamber 632 mechanically engages a moveable assembly ofactuator/motor 630 of the instrument system directly or indirectly viaone or more gears, worm screws, or friction engagements. The push/pullaction of the syringe pump is controlled by actuating actuator/motor630. Materials may be passed between pump chamber 632 and the selectedport of valve 606. For example, material may be pushed into chamber 632from a selected port of valve 606 and material in chamber 632 may bepushed out of chamber 632 to a selected port of valve 606.

In some embodiments, by delivering/pushing and drawing/pulling variousmaterials to/from the ports of radial valve 606 using the pump ofchamber 632 in a configured sequence, a biological assay is performedusing biochip 604. For example, a reagent to be delivered/pushed intochip 604 may be placed in chamber 632 by selecting one of selectableports 622-628 on valve 606 connected to a desired reagent/gas, pumpingcontent of the selected port into pump chamber 632, then selecting portselecting port 621 on valve 606 and pushing the content of pump chamber632 to chip 604.

Often in the sequence, a material flowed on chip 604 needs to bediscarded as a next material is flowed across chip 604 to exit thechamber of 604. Material in the chamber of chip 604 may be pushed out ofthe chamber via chamber port 651 and into waste container 638. Howeverin some cases, it may be desirable to be able to discard materialwithout flowing the material to be discarded completely across chip 604to exit via chamber port 651. In some embodiments, port 621 is selectedon valve 606 and material on the chip is pumped into pump chamber 632,then pushed out into waste container 638 via bypass channel path 654that does not enter the chamber of chip 604. Three-way valve 650 may beswitched to either connect port 621 with only the chamber of chip 604 orwith only bypass channel 654, as appropriate. In an alternativeembodiment, rather than using three-way valve 650, the chamber of chip604 is always connected to port 621 (e.g., without three-way valve 650)and a bypass selectable port on radial valve 606 (e.g., alternativeembodiment shown as selectable port 660) is always connected to bypasschannel 654 to allow a connection between pump chamber 632 and wastecontainer 638 without passing through the chamber of chip 604 when thebypass selectable port is selected. Other materials pumped from othersources (e.g., during initial priming) by the pump of chamber 632 to bediscarded may also be pushed into waste container 638 via bypass channel654. Examples of waste container 638 include a vented container, anexpandable container, a one-way valve container, and an absorbentmaterial filled container. Two-way valve 652 may be configured to switchbetween allowing or not allowing flow between its connected channels. Byopening valve 652, material in the chamber of chip 604 may be directlypushed out into waste container 638. By closing valve 652, backflow onto chip 604 may be prevented when pushing waste into container 638 viabypass channel 654 or when waste content leaks out of waste container638. The ability to close valve 652 may also enable the pump topressurize the fluid or gas on chip 604. In some embodiments, valve 652is optional. In an alternative embodiment, valve 652 is a one-way valve.

The embodiment shown in FIG. 6 is merely an example and has beensimplified to illustrate the embodiment clearly. For example, the radialvalves shown in FIG. 6 may include any number of selectable ports.Additional components such as other valves not shown in FIG. 6 may alsoexist. In some embodiments, linear valve 700 is included in cartridge502 of FIG. 5. In some embodiments, linear valve 700 is included incartridge 602 or FIG. 6.

FIGS. 7A-7C are schematic diagrams illustrating another embodiment of atleast a portion of a biological sensor cartridge system. For example,the biological sensor cartridge system is a nanopore-based nucleotidesequencing system.

The sensor system includes cartridge 702. Cartridge 702 engages with aninstrument system, interfaces with the instrument system, and functionstogether with the instrument system to perform a biological assay (e.g.,nanopore-based nucleotide sequencing). The bottom side of cartridge 702may expose electrical contacts that allow electrical connection betweenone or more electrical components of cartridge 702 and the instrumentsystem to be engaged with cartridge 702. The electrical contacts of thecartridge electrically interfaces with the instrument system viaelectrical connector 755. Cartridge 702 is removable from the instrumentsystem and another cartridge may be engaged with the instrument system.By utilizing a removable cartridge, the components of the cartridge maybe replaced quickly and easily on the instrument system without the needto clean and reuse the components of the cartridge. For example, thecartridge may be replaced for each different biological sample to beassayed by the instrument system.

Cartridge 702 includes biochip 704, radial valve 706, and containers708, 710, 712 and 740 that are vented. Each of containers 708, 710, 712and 740 may hold a liquid, a reagent, a gas, a solid (e.g., suspended inliquid), and any other substance to be utilized in performing abiological measurement. For example, container 708 holds a lipid anddecane mix, container 710 holds a sample and pore/polymerase mix,container 712 holds a StartMix and container 740 is a reserved sparecontainer. In some embodiments, at least container 710 and container 712are sensitive to temperature changes and TEC/heat sink assembly 742provides thermal heating and/or cooling to raise, lower, and/or maintaina temperature of contents of container 710 and container 712. Containers708, 710, 712 and 740 are each connected to a different selectable portof radial valve 706. The channel paths connecting each container to acorresponding selectable port includes a pipette input that can beutilized to deliver material to the corresponding container and/orselectable port.

Biochip 704 may be the nanopore-based sequencing chip describedelsewhere in the specification. Biochip 704 is electricallyconnected/interfaced with the instrument system via electrical connector755 and electrical measurement data is read from biochip 704 andexported out of the biochip 704 to the instrument system forstorage/analysis. Biochip 704 is thermally coupled to the instrumentsystem via TEC/heat sink assembly 716. TEC/heat sink 716 allows thermalenergy of biochip 704 to be dissipated via assembly 716.

Radial valve 706 mechanically engages actuator/motor 718 of theinstrument system. Actuator/motor 718 is separate from cartridge 702.Motor 718 actuates a movable assembly of radial valve 706 to select oneor more desired port of radial valve 706. For example, motor 718 engagesa movable assembly of radial valve 706 directly or indirectly via one ormore gears, worm screws, or friction engagements (e.g., friction wheel).

Radial valve 706 includes central port 720 and can be placed in any oneof shown selectable positions 1-8 that are arranged coaxially in arotary configuration. Radial valve 706 is rotated via actuator/motor 718to select one of selectable positions 1-8. Positions 3-6 each correspondto a different selectable port that can be selected as the connectedactive/open port. The other not selected ports are automaticallysealed/closed when the selected port is selected. Using positions 1 and2 on radial valve 706, a direct connection between outlet port 735 ofthe chamber of chip 704 and port 736 connected to a waste container iscontrolled in addition to controlling a separate direct connectionbetween central port 720 and the inlet port of the chamber of chip 704.In some embodiments, by allowing a single selectable valve to control aconnection that does not directly involve its central port, a moreefficient cartridge design may be achieved due to the multiple functionsbeing performed by the selectable valve. For example, rather using valve652 of FIG. 6, a single selectable valve such as valve 706 may beutilized to perform the functions of both radial valve 606 and valve 652of FIG. 6.

The exact position of radial valve 706 is determined using opticalencoder 760. For example, by reading/detecting a pattern on a moveableassembly of radial valve 706, optical encoder 760 converts the detectedpattern corresponding to a specific position of the moveable assembly toan electrical signal/code that can be utilized to determine the specificposition. In an alternative embodiment, rather than utilizing an opticalencoder, a known “home” position of the radial valve is identified andan open loop control is utilized to rotate the radial valve a controlledamount (e.g., specified number of degrees). Channel 722 of radial valve706 connects central port 720 to the selectable port (e.g., channel 722has multiple selection ports as shown by circles on channel 722). When amoveable assembly of valve 706 is rotated, channel 722 is physicallyrotated together. In addition to channel 722, channel 724 is also movedwhen the moveable assembly of valve 706 is rotated. However, channel 724is not directly connected to central port 720.

FIG. 7A shows radial valve 706 in position “1.” In this position,central port 720 is connected to a selectable port that is connected tothe inlet port (e.g., two-way port) of the chamber of chip 704, allowingmaterials to be passed between central port 720 and the chamber of chip704. However, channel 724 does not connect any ports in position “1.”Thus, chamber outlet port 735 of the chamber of chip 704 is sealed andnot connected to port 736 of the waste container. This may allow chip704 and contents of the chamber to be pressurized. FIG. 7B shows radialvalve 706 in position “2.” In this position, channel 722 still connectscentral port 720 with the selectable port that is connected to the inletport of the chamber of chip 704, allowing materials to be passed betweencentral port 720 and the chamber of chip 704. However, channel 724 nowconnects chamber outlet port 735 of the chamber of chip 704 with port736 of the waste container, allowing waste to flow from the chip chamberto the waste container. FIG. 7C shows radial valve 706 in position “3.”In this position, channel 722 connects central port 720 with theselectable port that is connected to an air vent. Channel 724 does notconnect any ports in position “3.”

Central port 720 is connected to interface 728 via a channel (e.g.,tube). Interface port 728 is an interface of cartridge 702 wherematerials may enter/exit cartridge 702. In the example shown, a needleseptum is utilized as the interface port. Central port 720 is connectedto pump 730 via interface 728. Pump 730 includes a syringe pump that maydraw or push content into or out of pump chamber 732. Pump 730 includesa secondary radial value. In some embodiments, chamber 732 is a fluidicchannel such as tubing. Pump 730 is a two-way pump that can deliver/pushand draw/pull materials in to/out of pump chamber 732. In someembodiments, pump 730 functions in a similar manner as pump 530 of FIG.5. Position “8” of radial valve 706 corresponds to a selection of abypass waste selectable port that allows a connection between centralport 720 and a waste container without passing through the chamber ofchip 704 when the bypass waste selectable port is selected.

FIG. 8A is a diagram illustrating an embodiment of a cartridge. In someembodiments, cartridge 802 is cartridge 502 of FIG. 5. In someembodiments, cartridge 802 shows at least a portion of features ofcartridge 602 of FIG. 6 and/or cartridge 702 of FIG. 7.

The bottom side of cartridge 802 exposes electrical contacts 804.Electrical contacts 804 allow electrical connection between one or moreelectrical components of cartridge 802 and an instrument system to beengaged with cartridge 802. For example, electrical data (e.g.,electrical measurement/reading data) of the biochip may beaccessed/provided/received via electrical contacts 804 by the instrumentsystem to determine a result of a biological assay. In some embodiments,electrical contacts 804 are contacts of a circuit board included incartridge 802 and the circuit board is electrically connected to abiochip.

Thermal chip interface 806 provides a thermal interface where a heatsink (e.g., heat sink 516 of FIG. 5 or heat sink 616 of FIG. 6) can bethermally coupled to a biochip included in cartridge 802. For example,the heat sink allows thermal energy of the biochip to be dissipated viathe heat sink. The heat sink may be a part of the instrument system thatreceives cartridge 802. Cartridge 802 includes interface port 808 andinterface port 810. In some embodiments, interface port 808 is interfaceport 528 of FIG. 5. In some embodiments, interface port 808 is connectedto a central port of a radial valve (e.g., connected port 520 of FIG. 5or port 620 of FIG. 6) and/or a syringe pump. In some embodiments,interface port 810 is interface port 536 of FIG. 5. In some embodiments,interface port 810 is a waste port. Drive engagement port 812 isconfigured to engage with an actuator/motor to operate a selectablevalve. For example, a selection of a selected valve among a plurality ofselectable valves is performed by mechanically actuating an engagementmechanism (e.g., gear) exposed in motor drive engagement port 812. Insome embodiments, motor drive engagement port 812 is utilized to selecta selectable port of a radial valve (e.g., radial valve 506 of FIG. 5 orvalve 606 of FIG. 6). In some embodiments, motor drive engagement port812 is utilized to select a selectable port of a linear valve (e.g.,linear valve 700 of FIG. 7).

Cartridge 802 includes thermally controlled containers 814 and 816.Container 818 is not to be thermally controlled. Containers 814, 816,and 818 may hold a liquid, a reagent, a gas, a solid (e.g., suspended inliquid), and any other substance to be utilized in performing abiological measurement. For example, container 814 holds a StartMix andcontainer 816 holds a sample and pore/polymerase mix and container 818holds a lipid and decane mix. Contents of containers 814, 816, and 818are connected to selectable ports of a selectable valve via separatechannels and the contents of the containers may be drawn for use duringa biological assay via the corresponding selectable valve. Containers814 and 816 may be thermal-controlled using a thermal block (e.g.,thermally controlled using refrigerant, ice, Freon, thermal-electric,etc.) that surrounds at least a portion of containers 814 and 816 toreduce and/or maintain a temperature of its contents (e.g., via thermalconduction through walls of containers 814 and 816). In someembodiments, a thermal conductive material probe (e.g., metal rod) isplaced within container 814 and/or container 816 and the probe isthermal-controlled (e.g., immersion cooled/heated via an externalcool/heat source thermally coupled to the probe (e.g., probe extendsthrough cap of the container such that the probe is partly immersed incontents of the container and partly exposed outside the container wherethe external thermal source may be coupled)).

FIG. 8B is a diagram illustrating an embodiment of at least a portion ofinternal components of a cartridge. In some embodiments, one or morecomponents shown in FIG. 8B are included cartridge 502 of FIG. 5,cartridge 702 of FIG. 7 and/or cartridge 602 of FIG. 6.

The cartridge includes circuit board 820. Circuit board 820 iselectrically coupled to biochip 828. In various embodiments, biochip 828is biochip 504 of FIG. 5 and/or biochip 604 of FIG. 6. The bottom sideof circuit board 820 includes electrical contacts 804 shown in FIG. 8A.The cartridge of FIG. 8B includes a radial valve. The radial valvecomprises a port selector assembly 822. Selectable ports 824 arearranged coaxially in a rotary configuration on body assembly 825 thatremains stationary while selector assembly 822 is rotated to select oneof selectable ports 824 as the selected connected port. For example,port selector assembly 822 may be rotated using an externalactuator/motor to select one of selectable ports 824 as a selected portthat will be connected via a channel on selector assembly 822 to centralport 821.

Central port 821 is connected to interface port 808 where a two-way pumpmay be coupled. By rotating selector assembly 822 to a specific locationon assembly 825 where connector port 823 becomes aligned with a desiredone of selectable ports 824, a channel between the selected port andcentral port 821 is established while the other not selected ports ofselectable ports 824 become sealed by selector assembly 822. In someembodiments, selector assembly 822 includes a mechanical interface(e.g., gear) that is included in or mechanically coupled to gears 826.Selector component 822 is rotated using gears 826 that are mechanicallyengaged with an actuator via engagement port 812 shown in FIG. 8A.

FIG. 8C is a diagram illustrating an embodiment of a cartridge and aninstrument system that engages the cartridge. In some embodiments,cartridge 802 is cartridge 502 of FIG. 5. In some embodiments, cartridge802 shows at least a portion of features of cartridge 602 of FIG. 6and/or cartridge 702 of FIG. 7.

Cartridge 802 may be pushed down and received by instrument 830 toengage cartridge 802 with instrument 830. Cartridge 802 may be removedfrom instrument 830 after use and another cartridge may be engaged withinstrument 830 for a different sample. In some embodiments, instrument830 is at least a portion of a system utilized to perform a biologicalassay (e.g., nucleotide sequencing). Instrument 830 includes maleconnectors 832 that can be coupled with electrical contacts 804 shown inFIG. 8A. Electrical connections between a biochip included in cartridge802 and one or more electrical components of instrument 830 areestablished via male connectors 832. Instrument 830 includes heat sink834. Heat sink 834 can be thermally coupled to a biochip via thermalinterface 806 of FIG. 8A. Examples of heat sink 834 include heat sink516 of FIG. 5 and heat sink 616 of FIG. 6. Thermal block 836 (e.g., coldblock) of instrument 830 is configured to surround at least a portion ofcontainers 814 and 816 and provide a thermal source to thermally control(e.g., cool/heat) the contents of containers 814 and 816. Thermal block836 is surrounded by thermal insulation 838 to maintain thermal energyof thermal block 836. In some embodiments, when cartridge 802 is engagedwith instrument 830, cartridge 802 and instrument 830 are mechanicallyclamped together using one or more clamps.

FIG. 9 is a diagram illustrating another embodiment of at least aportion of internal components of a cartridge. In some embodiments, thecartridge components shown in FIG. 9 are included in cartridge 702 ofFIG. 7. In some embodiments, one or more of the cartridge componentsshown in FIG. 9 are included in cartridges 502 and/or 602 of FIGS. 5 and6.

The cartridge includes circuit board 920. Circuit board 920 iselectrically coupled to biochip 928. In various embodiments, biochip 928is biochip 504 of FIG. 5, biochip 604 of FIG. 6 and/or biochip 704 ofFIG. 7. The cartridge of FIG. 9 includes a radial valve. The radialvalve comprises port selector assembly 922. Selectable ports are engagedon both sides of port selector assembly 922. Port selector assembly 922selector seals and connects ports on both the top (e.g., going to thereagents via upper seal plate assembly 924) and bottom (e.g., going tothe chip via lower seal plate assembly 926) of assembly 922. Portselector assembly 922 is positioned on top of chip 928 and is orientedsuch that an inlet of the chamber of the chip is positioned along aninner ring of ports on lower seal plate assembly 926 and the outlet ofthe chamber of the chip is positioned along an outer ring of ports onlower seal plate assembly 926. By rotating selector assembly 922 tospecific locations on assemblies 924 and 926 where connector ports onselector assembly 922 becomes aligned with desired connector port(s) onupper seal plate assembly 924 and lower seal plate assembly 926, one ormore desired channel connections are created while other connector portsmay be sealed. For example, in one position, both inlet and outlet portsof the chamber of the chip are open, allowing fluid flow through thechip. In a second position the inlet is open, but the outlet is blocked,allowing the fluid inside the chip to be pressurized (e.g., part oflipid bilayer formation protocol). In some embodiments, port selectorassembly 922 includes channels 722 and 724 of FIG. 7. Manifold plateassembly 928 includes containers/reservoirs, a waste container and/orchannels. Selector assembly 922 includes a mechanical interface (e.g.,gear) that is included in or mechanically coupled to drive gears of anactuator/motor. Upper seal plate assembly 924 and lower seal plateassembly 926 remain stationary while selector assembly 922 is rotated toa desired position.

FIG. 10 is a schematic diagram illustrating an embodiment of a linearvalve. In some embodiments, rather than utilizing radial valve 506 ofFIG. 5, radial valve 606 of FIG. 6, or radial valve 706 of FIG. 7,linear valve 1000 may be utilized in its place. Selector assembly 1002moves along track 1012 to select one of selectable ports 1006-1011 to beconnected to central port 1004. For example, a motor moves selector 1002along track 1012 to one of a plurality of specific locations on astationary assembly that each correspond to one of selectable ports1006-1011. At each location of track 1012 of the stationary assemblythat corresponds to a specific selectable port, an opening connected tothe specific selectable port is able to be connected to central port1004 when selector 1002 is moved to the specific location correspondingto the specific selectable port. In the example shown, selector 1002 isat a location of track 1012 corresponding to selectable port 1008. Inanother example, selector assembly 1002 may be moved to the positionoutlined as 1020 to select port 1010. The motor may be a part of aninstrument while linear valve 1000 is a part of a separate removablecartridge that engages with the instrument. Selector assembly 1002 maybe moved by the motor directly or indirectly via one or more gears, wormscrews, pistons, friction engagements, or belts.

When one of selectable ports 1006-1011 is selected by selector 1002 asthe active/open port (e.g., selector 1002 is moved to a location ontrack 1012 corresponding to the selected port), other not selected portsof selectable ports 1006-1011 are automatically sealed/closed when theselected port is selected. Materials may be passed between central port1004 and the selected port. For example, a fluid/gas passage channel iscreated between central port 1004 and the selected port. Central port1004 may be connected to a syringe pump (e.g., connected to pump 530 ofFIG. 5, pump 730 of FIG. 7 or to pump of chamber 632 of FIG. 6). Each ofselectable ports 1006-1011 may be connected to different reagents,gasses, vents, waste containers, cleaning solutions, biological samples,channels, etc. via separate corresponding channels. For example,materials/components utilized in performing a biological assay areconnected to the selectable ports. The number of ports and/or the shapeof the linear valve shown in FIG. 10 is merely an example. Any number ofports and selectable valve shapes may exist in various embodiments.

FIG. 11 is a flowchart illustrating an embodiment of a process forflowing different types of materials (e.g., liquids or gases) throughthe cells of a nanopore-based sequencing biochip during different phasesof the biochip operation. The nanopore-based sequencing biochip operatesin different phases, including an initialization and calibration phase(phase 1102), a membrane formation phase (phase 1104), a nanoporeformation phase (phase 1106), a sequencing phase (phase 1108), and acleaning and reset phase (phase 1110). In some embodiments, the biochipof FIG. 11 includes cell 100 of FIG. 1. In some embodiments, the biochipof FIG. 11 is biochip 504 of FIG. 5. In some embodiments, the biochip ofFIG. 11 is biochip 604 of FIG. 6. In some embodiments, the biochip ofFIG. 11 is biochip 704 of FIG. 7.

At the initialization and calibration phase 1102, a salt buffer solutionis flowed through the cells of the nanopore-based sequencing chip at1112. The salt buffer solution may be potassium choloride (KCl),potassium acetate (KAc), sodium trifluoroacetate (NaTFA), and the like.In some embodiments, performing step 1112 using cartridge 602 of FIG. 6includes using actuator/motor 618 to rotate radial valve 606 to selectport 627, drawing KCl into syringe pump chamber 632 using motor 630,using motor 618 to rotate radial valve 606 to select port 621, andpushing out the KCl in pump chamber 632 to the chamber of biochip 604via selected port 621. In some embodiments, when a cartridge (e.g.,cartridge 502 or FIG. 5 or cartridge 602 of FIG. 6) is utilized inperforming the process of FIG. 11, the cartridge is primed for initialuse. For example, various materials connected to selectable ports of aselectable valve are primed to draw materials through channels to theselecteable ports for use during the process. Excess materials drawnduring priming may be discarded to a waste container (e.g., waste 638via bypass channel 654 of FIG. 6).

At the membrane formation phase 1104, a membrane, such as a lipidbilayer, is formed over each of the cells. At 1114, a lipid and decanemixture is flowed over the cells. In some embodiments, flowing the lipidand decane mixture includes flowing an air buffer (e.g., air bubble)prior to and after flowing the lipid and decane mixture. Using theexample of FIG. 6 to perform step 1114, actuator/motor 618 is used torotate radial valve 606 to select port 628, air from vent of selectableport 628 is drawn into pump chamber 632 using pump motor 630, motor 618is used to rotate radial valve 606 to select port 624, a lipid anddecane mixture is drawn into chamber 632, motor 618 is used to rotateradial valve 606 to select port 628, air is again drawn into pumpchamber 632 using pump motor 630, motor 618 is used to rotate radialvalve 606 to select port 621, and then the combination of air buffer,mixture and another air buffer in pump chamber 632 is pushed to thechamber of biochip 604 via selected port 621. As material is flowed overthe biochip, the materials that have already flowed across the biochipare pushed into a waste container after exiting the chamber of thebiochip.

At 1116, a salt buffer solution is flowed over the cells first, and thenan air bubble is flowed over the cells. In an example utilizing aselectable valve, a particular selectable port connected to a saltbuffer solution container is selected to draw the salt buffer solutioninto a pump chamber and another selectable port is selected to draw theair bubble into the pump chamber before pushing the salt buffer and/orair bubble into the chamber of the biochip. One of the purposes offlowing an air bubble over the cells is to facilitate the formation ofthe lipid bilayer over each of the cells. When an air bubble is flowedover the cells, the thickness of the lipid and decane mixture depositedon the cell is reduced, facilitating the formation of the lipid bilayer.

At 1118, voltage measurements across the lipid bilayers are made todetermine whether the lipid bilayers are properly formed. If it isdetermined that the lipid bilayers are not properly formed, then step1116 is repeated; otherwise, the process proceeds to step 1120. At 1120,a salt buffer solution is again introduced, and a final air bubble isflowed over the cells. For example, a previously described selectablevalve is utilized to draw and push the salt buffer and the air bubble asappropriate from various selectable ports by pushing a combination of anair bubble sandwiched between salt buffer solutions to biochip 604.

At the nanopore formation phase 1106, a nanopore is formed in thebilayer over each of the cells. At 1122, a sample and a pore/polymerasemixture are flowed over the cells. In some embodiments, performing step1122 using cartridge 602 of FIG. 6 includes using actuator/motor 618 torotate radial valve 606 to select port 623, drawing a sample andpore/polymerase mixture into pump chamber 632, using motor 618 to rotateradial valve 606 to select port 621, and pushing out the mixture in pumpchamber 632 to the chamber of biochip 604 via selected port 621. Inorder to not disturb the bilayer that has been formed in phase 1104, anair buffer is not introduced between the ending salt buffer solution of1120 and the sample and pore/polymerase mixture of 1122. In someembodiments, rather than disturbing the nanopore that has been formed byallowing the sample and pore/polymerase mixture to flow completelyacross the chamber of a biochip and into a waste container, the mixtureis pulled from the chamber of the biochip from the chamber opening wherethe mixture was introduced and the pulled mixture is discarded via abypass port/channel that does not traverse the chamber of the biochip.For example, using cartridge 602 of FIG. 6, radial valve 606 isconfigured to select port 621, the sample and pore/polymerase mixture inthe chamber of biochip 604 is drawn into pump chamber 632, radial valve606 is actuated to select port 660 (e.g., in the embodiment of FIG. 6where bypass channel 654 is directly connected to radial valve 606 viaport 660 and valve 650 is replaced with a direct connection between port621 and the chamber of biochip 604), and the content of pump chamber 632is discarded to waste container 638 via bypass channel 654 withoutflowing through chamber port 651.

At sequencing phase 1108, a biological assay (e.g., DNA sequencing) isperformed. At 1124, StartMix is flowed over the cells, and thesequencing information is collected and stored. StartMix is a reagentthat initiates the sequencing process. In some embodiments, performingstep 1124 using cartridge 602 of FIG. 6 includes using actuator/motor618 to rotate radial valve 606 to select port 622, drawing StartMix intosyringe pump chamber 632, using motor 618 to rotate radial valve 606 toselect port 621, and pushing out the StartMix in pump chamber 632 tobiochip 604 via selected port 621. In order to not disturb the bilayerand nanopore that has been formed, an air buffer is not introducedbefore the StartMix. After the sequencing phase, one cycle of theprocess is completed at 1126.

At the cleaning and reset phase 1110, the nanopore-based sequencingbiochip is cleaned and reset such that the chip can be recycled foradditional uses. For example, a biological assay (e.g., DNA sequencing)of the same sample is performed again. At 1128, a surfactant is flowedover the cells. At 1130, ethanol is flowed over the cells. Although asurfactant and ethanol are used for cleaning the chip in thisembodiment, alternative fluids may be used in other embodiments. Steps1128 and 1130 may also be repeated a plurality of times to ensure thatthe chip is properly cleaned. In various embodiments, one or morecleaning fluids are obtained via one or more selectable ports of aselectable valve (e.g., radial valve 606 of FIG. 6) to be pushed andflowed over the biochip to be cleaned. After step 1130, the lipidbilayers and pores have been removed and the fluidic workflow process1100 can be repeated at the initialization and calibration phase 1102again.

As shown in process 1100 described above, multiple materials withsignificantly different properties (e.g., compressibility,hydrophobicity, and viscosity) are flowed over an array of sensors onthe surface of the nanopore-based sequencing biochip. For improvedefficiency, each of the sensors in the array should be exposed to thefluids or gases in a consistent manner. For example, each of thedifferent types of fluids should be flowed over the nanopore-basedsequencing chip such that the fluid or gas may be delivered to the chip,evenly coating and contacting all of the cells' surface, and thendelivered out of the chip. As described above, a nanopore-basedsequencing biochip incorporates a large number of sensor cellsconfigured as an array. As the nanopore-based sequencing chip is scaledto include more and more cells, achieving an even flow of the differenttypes of fluids or gases across the cells of the chip becomes morechallenging. Although examples related to FIG. 6 have been discussed inconjunction with the process of FIG. 11, in various embodiments, otherselectable ports and cartridges (e.g., using the components of theexamples of FIGS. 5, 7, 8A-8C, 9 etc.) may be utilized to implement theprocess of FIG. 11.

Although the foregoing embodiments have been described in some detailfor purposes of clarity of understanding, the invention is not limitedto the details provided. There are many alternative ways of implementingthe invention. The disclosed embodiments are illustrative and notrestrictive.

What is claimed is:
 1. A sequencing system, the system comprising: aremovable cartridge comprising a sequencing chip and a flow celldisposed over the sequencing chip to form a fluid chamber over thesequencing chip, the sequencing chip comprising an array of sensorcells, the flow cell comprising a flowcell inlet and a flowcell outlet;a plurality of selectable ports and a plurality of reservoirs, each portin fluid communication with one of the fluid reservoirs; a selectablevalve assembly that is selectively connectable to each of the selectableports, the selectable valve assembly also configured to be in fluidcommunication with the flowcell inlet; a pump in fluid communicationwith the selectable valve assembly such that the pump is configured toselectively withdraw fluid from one of the fluid reservoirs and directthe withdrawn fluid through the flowcell inlet into the fluid chamberover the sequencing chip when the selectable valve assembly isselectively connected to the selectable port in fluid communication withthe fluid reservoir; a waste reservoir in fluid communication with theflow cell outlet, wherein the pump is configured to direct fluid out ofthe fluid chamber through the flowcell outlet and into the wastereservoir.
 2. The sequencing system of claim 1, wherein the selectablevalve assembly is a rotary valve.
 3. The sequencing system of claim 1,wherein the selectable valve assembly is a linear valve.
 4. Thesequencing system of claim 1, wherein the plurality of fluid reservoirsincludes a first reservoir comprising a salt buffer solution, a secondreservoir comprising membrane forming solution, a third reservoircomprising a nanopore solution, and a fourth reservoir comprising acleaning solution.
 5. The sequencing system of claim 4, wherein thethird reservoir further comprises a sample to be sequenced.
 6. Thesequencing system of claim 4, wherein the plurality of reservoirsfurther includes a fifth reservoir comprising a sample to be sequenced.7. The sequencing system of claim 1, further comprising a cold blockconfigured to chill one or more of the reservoirs.
 8. The sequencingsystem of claim 1, further comprising a thermoelectric configured tocontrol the temperature of the sequencing chip when the removablecartridge is placed in the sequencing system.